Selected Grantee Publications
- 608 results found
Metabolomics Analysis of Follicular Fluid Coupled With Oocyte Aspiration Reveals Importance of Glucocorticoids in Primate Periovulatory Follicle Competency
Ravisankar et al., Scientific Reports. 2021.
https://www.nature.com/articles/s41598-021-85704-6
Assisted reproductive therapy in primates requires ovarian stimulation protocols, which result in multiple heterogeneous oocytes with variable capacity for fertilization, cleavage, and blastocyst formation. Recovered oocytes from rhesus macaque follicles (n=74 follicles) were fertilized in vitro and classified as failed to cleave, cleaved but arrested, or able to form blastocysts. Metabolomics analysis of the follicular fluid identified 60 metabolites that were different among embryo classifications; key was an increase in the intrafollicular ratio of cortisol to cortisone in the blastocyst group, which was associated with translocation of the glucocorticoid receptor, NR3C1. The data suggest a role for NR3C1 in the regulation of follicular processes, such as expansion of cumulus granulosa cells, via paracrine signaling. Supported by ORIP (P51OD011092) and NICHD.
Resident Memory T Cells Form During Persistent Antigen Exposure Leading to Allograft Rejection
Abou-Daya et al., Science Immunology. 2021.
https://www.science.org/doi/10.1126/sciimmunol.abc8122
It is not clear whether tissue-resident memory T cells (TRM) function in organ transplants where cognate antigen persists. This is a key question in transplantation as T cells are detected long term in allografts. Investigators showed that antigen-specific and polyclonal effector T cells differentiated in the graft into TRM and subsequently caused allograft rejection. Graft TRM proliferated locally, produced interferon-γ upon restimulation, and their in vivo depletion attenuated rejection. The vast majority of antigen-specific and polyclonal TRM lacked phenotypic and transcriptional exhaustion markers. Single-cell analysis of graft T cells early and late after transplantation identified a transcriptional program associated with transition to the tissue-resident state that could serve as a platform for the discovery of therapeutic targets. Thus, recipient effector T cells differentiate into functional graft TRM that maintain rejection locally. Targeting these TRM could improve renal transplant outcomes. Supported by ORIP (S10OD011925, S10OD019942).
A Novel Tau-Based Rhesus Monkey Model of Alzheimer’s Pathogenesis
Beckman et al., Alzheimer’s & Dementia. 2021.
https://pubmed.ncbi.nlm.nih.gov/33734581/
Alzheimer’s disease (AD) is becoming more prevalent as the population ages, but there are no effective treatments for this devastating condition. Researchers developed a rhesus monkey model of AD by targeting the entorhinal cortex with an adeno-associated virus expressing mutant tau protein. Within 3 months they observed evidence of misfolded tau propagation, similar to what is hypothesized for AD patients. Treated monkeys developed robust alterations in AD core biomarkers in cerebrospinal fluid and blood. These results highlight the initial stages of tau seeding and propagation in rhesus macaques, a potentially powerful translational model with which to test new AD therapies. Supported by ORIP (P51OD011107) and NIA.
A Platform for Experimental Precision Medicine: The Extended BXD Mouse Family
Ashbrook et al., Cell Systems. 2021.
https://www.sciencedirect.com/science/article/abs/pii/S2405471220305032
Systems genetics using rodent models has recently been revitalized thanks to several resources: the BXD family, the Hybrid Mouse Diversity Panel, and the Collaborative Cross. The main limitation has been modest mapping power and precision due to small strain numbers. Investigators expanded the BXD family of mice to 140 fully isogenic strains. Heritable traits can be mapped with precision. Current BXD phenomes include much omics data and thousands of quantitative traits. BXDs can be extended by a single-generation cross up to 19,460 isogenic F1 progeny. This extended BXD family is an effective platform for testing causal modeling and predictive validation. Supported by ORIP (P40OD011102).
A Pulsatile Release Platform Based on Photo-Induced Imine-Crosslinking Hydrogel Promotes Scarless Wound Healing
Zhang et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33723267/
Skin wound healing is a dynamic and interactive process involving the collaborative efforts of growth factors, extracellular matrix (ECM), and different tissue and cell lineages. Although accumulating studies with a range of different model systems have increased our understanding of the cellular and molecular basis underlying skin scar formation, they have not been effectively translated to therapy. Development of effective therapeutic approaches for skin scar management is urgently needed. In this study, team of investigators devise a water-oil-water double emulsion strategy to encapsulate proteins within a photo-crosslinkable poly-lactic-co-glycolic acid (PLGA) shell, which can produce microcapsules with pulsatile drug release kinetics after administration. The results show that pulsatile release of the TGF-β inhibitor can accelerate skin wound closure while suppressing scarring in murine skin wounds and large animal preclinical models, suggesting that it could be an effective approach to achieve scarless wound healing in skin. Supported by ORIP (R01OD023700).
Virus Control in Vaccinated Rhesus Macaques Is Associated with Neutralizing and Capturing Antibodies Against the SHIV Challenge Virus but Not with V1V2 Vaccine–Induced Anti-V2 Antibodies Alone
Hessell et al., Journal of Immunology. 2021.
https://doi.org/10.4049/jimmunol.2001010
In the RV144 human immunodeficiency virus (HIV) vaccine trial, the only immune response associated with reduced infection was a high level of antibodies (Abs) targeting the second variable (V2) loop of the HIV envelope protein (Env). The mechanism underlying this suggested contribution of V2 Abs to protection remains unknown. Researchers tested the role of vaccine-induced anti-V2 Abs in rhesus macaques. Three vaccines strategies were designed to induce only V1V2 Abs before simian-human immunodeficiency virus (SHIV) challenge. Vaccine-induced V2 Abs did not independently control SHIV infection. However, neutralizing and virus capture anti-Env Abs were found to correlate with SHIV control. Supported by ORIP (P51OD011092) and NIAID.
Creb5 Establishes the Competence for Prg4 Expression in Articular Cartilage
Zhang et al., Communications Biology. 2021.
https://doi.org/10.1038/s42003-021-01857-0
Cells comprising the superficial zone of articular cartilage express lubricin, encoded by the Prg4 gene, that lubricates joints. Researchers identified Creb5 as a transcription factor that is required for TGF-β and EGFR signaling to induce Prg4 expression. Forced expression of Creb5 in deep-zone chondrocytes of articular cartilage confers competence for TGF-β and EGFR signals to induce Prg4 expression. The researchers showed that Creb5 directly binds to two Prg4 promoter-proximal regulatory elements, which work together with a more distal regulatory element to drive induction of Prg4 by TGF-β. Thus, Creb5 is a critical regulator of Prg4/lubricin expression in the articular cartilage. Supported by ORIP (U42OD11158), NIAMS, and NIDDK.
Persistence of Viral RNA in Lymph Nodes in ART-suppressed SIV/SHIV-Infected Rhesus Macaques
Cadena et al., Nature Communications. 2021.
https://doi.org/10.1038/s41467-021-21724-0
The long-lived viral reservoir is a key obstacle to curing HIV/AIDS, yet the features of that reservoir during antiretroviral therapy (ART) remain poorly understood. Researchers undertook a comprehensive analysis of the SIV/SHIV reservoir in multiple lymphoid and non-lymphoid tissues from SIV/SHIV-infected rhesus macaques suppressed with ART for one year. Their findings support a model in which the tissue viral reservoir is rapidly and broadly seeded early during acute infection. Viral RNA persists lymphoid tissues despite a long period of suppressive ART. Therefore, viral latency does not appear to be universally transcriptionally silent; the reservoir may include a spectrum of latency depths. Supported by ORIP (R01OD024917) and NIAID.
A Chromosome-Level Genome of Astyanax mexicanus Surface Fish for Comparing Population-Specific Genetic Differences Contributing to Trait Evolution
Warren et al., Nature Communications. 2021.
https://pubmed.ncbi.nlm.nih.gov/33664263/
Identifying the genetic factors that underlie complex traits is central to understanding the mechanistic underpinnings of evolution. Cave-dwelling Astyanax mexicanus populations are well adapted to subterranean life and many populations appear to have evolved troglomorphic (morphological adaptation of an animal to living in the constant darkness of caves) traits independently, while the surface-dwelling populations can be used as a proxy for the ancestral form. Warren et al. present a high-resolution, chromosome-level surface fish genome, enabling the first genome-wide comparison between surface fish and cavefish populations. Using this resource, they performed quantitative trait locus (QTL) mapping analyses and found new candidate genes for eye loss (dusp26). They also generated the first genome-wide evaluation of deletion variability across cavefish populations to gain insight into this potential source of cave adaptation. The surface fish genome reference now provides a more complete resource for comparative, functional and genetic studies of drastic trait differences within a species. Supported by ORIP (R24OD011198), NIA, NICHD, NIGMS, amd NIDCR.
New SHIVs and Improved Design Strategy for Modeling HIV-1 Transmission, Immunopathogenesis, Prevention, and Cure
Li et al., Journal of Virology. 2021.
https://doi.org/10.1128/JVI.00071-21
Researchers knew that substitution of HIV-1 Env residue 375-serine by aromatic residues enhances binding to rhesus CD4 enabling primary HIV-1 Envs to support replication as simian-human immunodeficiency virus (SHIV) chimeras in rhesus monkeys. The investigators constructed SHIVs containing 10 primary Envs corresponding to HIV-1 subtypes A, B, C, AE, and AG. Only one with histidine at Env375 replicated efficiently in rhesus cells. Replacement of wild-type Env375 residues by tryptophan, tyrosine, phenylalanine, or histidine in the other 9 SHIVs led to efficient replication. These new SHIVs transmit via mucosal routes like HIV-1 and have use for vaccine testing in nonhuman primates. Supported by ORIP (U42OD021458, P40OD012217), NIAID, and NCI.